Oral infections of Candida albicans represent an increasing problem in human health. In immunocompromised individuals, especially those suffering from AIDS, candiasis can result in both localized, yet painful lesions in the oral cavity as well as life-threatening systemic infections. Furthermore, due to the use of standard antifungal treatments, an increasing number of infections are due to non-albicans candidal (NAC) species. It is thus critical to develop new therapies that can treat both C. albicans infections as well as those due to NAC. Antimicrobial peptides (AMPs) are naturally occurring, broad-spectrum antimicrobial agents that have been examined recently for their utility as therapeutic antibiotics and antifungals. Chief among their strengths is that microbes do not generally develop resistance to these agents. Unfortunately, they are expensive to produce and are often sensitive to protease digestion. Polymedix, Inc. has developed a series of inexpensive nonpeptidic oligomers and polymers that mimic AMPs in both structure and activity. In the first phase of this grant, we examined a series of small molecule non-peptide mimics of AMPs and evaluated their potential as leads for a topical treatment for oral candidiasis. Our results demonstrated the potent activity of several classes of these mimetics against C. albicans as well as non-albicans species in both planktonic and biofilm cultures. The activity was rapid, and fungicidal against both blastoconidia and hyphal forms. We have also failed to generate resistant strains of Candida, substantiating their value as attractive candidates for anti-candidal drugs. To continue the development of candida-active mimetics, we propose the following aims for this Phase 2 application: 1). Establish a mouse model of oral candidal infection. 2) Define the activity of peptide mimetic compounds identified in phase I on oral candidal infection in vivo. 3) Optimize the mimetic chemistry to achieve the most active compound. Our overall goal in this phase is to determine the optimal compound(s) and conditions under which an antimicrobial peptide mimetic can be applied to oral mucosa in order to efficiently clear an experimental Candida infection. Successful completion of this phase will provide a development lead candidate(s) for further development as a topical treatment for oral candidiasis. PUBLIC HEALTH RELEVANCE: Oral candidal infections are serious complications found in immunocompromised individuals, such as those suffering from AIDS. Development of safe and effective agents to treat these painful and sometimes life-threatening infections, without the risk of developing resistant strains of Candida, is essential. We propose to examine several compounds determined in the first phase to be active against Candida, in an animal model of oral candidiasis to provide the basis for development of a treatment for this disease.